1. Field of the Invention
This invention relates to a novel biocompatible material, particularly an antithrombic medical material excellent in resistance to thrombus and in tissue-biocompatibility and therefore useful in artificial blood vessels, artificial internal organs, and catheters, to artificial internal organs and artificial blood vessels using the medical material, and to a method for the production thereof.
2. Description of the Prior Art
In the field of medical materials, numerous synthetic polymer materials such as polyesters, polyethylene, polypropylene, and polyurethane have found utility and have been producing numerous appreciable results. When they are used as medical materials such as, for example, artificial blood vessels which are destined to be exposed directly to blood, they cause coagulation of blood and induce thrombus. For the solution of this problem, various devices have been developed for the impartation of antithrombic quality to these polymer materials. For example, a method which comprises chemically binding such a natural anticoagulant substance as heparin to the surface of a given material (Japanese Patent Laid-Open SHO 51 (1976)-103,190) and a method which comprises endowing a given polymer substance with a synthetic radiolytically active compound as 1,2-diphenyl-3 or 5-dioxypyrazoline derivative (Japanese Patent Laid-Open SHO 52 (1977)-(142,772) have been known to the art. The heparin now in use has no perfect biocompatibility because it is an anticoagulant substance mainly obtained from the internal organs of swine or other similar animals other than human beings. Moreover, the process of binding the heparin to a polymeric carrier entails an unsettled problem that the heparin is divested of its activity when it is joined to the polymeric carrier by virtue of a covalent bond. Efforts have been made for the solution of this problem. For example, the observation of highly preferable antithrombic quality exhibited by a polymer made to incorporate therein heparin by ionic bonding and applied in the form of a coating on the surface of a given polymer material has been reported in literature (Shoji Nagaoka et al, "Artificial Internal Organs," Vol. 17 No. 2, pages 598-601, 1983) and the fact that a ternary block copolymer, polystyrene-PEO-heparin, incorporating therein heparin as one of the microdomains was synthesized and tested for antithrombic quality has been reported (Vulic, I. Transactions of 13th Annual Meeting of Society for Biomaterials, Page 81, 1987). For use as artificial blood vessels, these materials are still short of practical utility and none of them prove to be satisfactory. Urokinase, a thrombolytic enzyme, is extensively utilized clinically as a medicine for thrombosis. In the blood in circulation, however, the action of urokinase is suppressed because such plasmin inhibiting factors such as .alpha..sub.2 -plasmin inhibitor and .alpha..sub.2 -macroglubulin are abundantly contained in the blood. It is not recognized to produce the effect expectable from its in vitro activity. It is known that beside the method for conferring antithrombic quality on the polymer materials, a method for rendering the materials themselves unsusceptible to thrombosis has been studied on a series of segmented polyurethane systems. The method of study by molecular design has been tried on the basis of the conventional trial and error method. Concerning microdomain polymers, the research has been approaching the point of clearly establishing the relation between their phase separating property and antithrombic quality (Atsushi Miyahara et al. "Glossary of Abstracts of 18th Medical Polymer Symposium," page 21, 1987). A method using porous polyurethane resin as a material has been studied (Martz, H. et al. "Biomaterials," 8. 3, 1987). In this case, the material has not yet been fully developed to the extent of deserving practical utility because the material, on being transplanted, either fails to induce the covering of intima or induces it only very slowly (Koichi Tamura et al. "Artificial Internal Organs," 16, 1500, 1987).
Concerning these studies, reports purporting generally to express that artificial blood vessels made of such materials are able to inhibit initial thrombosis and produce satisfactory results for brief periods following their transplantation but, during a protracted use over a period exceeding one month, they are more often than not clogged and that the clogging is ascribable to imperfect covering of intima have been published one after another (Shinichi Sato et al. "Journal of Japan Surgical Society," pages 89-109, 1988; Yoshitatsu Kubo et al. "Angiology," 27, 8, pages 567-571, 1987; Norio Morimoto et al. "Artificial Internal Organs," 14, pages 941-944, 1985; and Zempei Sakai et al. "Artificial Internal Organs," 15, pages 367-370, 1986). The view that the efforts relying solely on synthetic polymer materials for simultaneous impartation of antithrombic quality and early covering of intima therapy have their limits has come to prevail. In the circumstances, methods for positively promoting the covering of intima as what may be called hybrid type artificial blood vessels, e.g. a method which comprises superposing a collagen layer on the surface of a macromolecular material (Japanese Patent Publication SHO 61(1986)-58,196) and a method which comprises cross-linking to natural blood vessels polyglycerol-polyglycidyl ether (PGPGE) containing epoxy groups as reactive groups in the side chain and at the terminal thereof, are now under study. They have much yet to be developed in the future.
The use of conventional organs formed solely of natural tissues has a problem of kinetic nature that they undergo cancerous ampliation after a protracted retention in the living body. It also has the possibility of retarding the covering of intima because the use of heparin curbs the growth of cells (Wolfgang Laukes et al. "Biochem. J.," 251, pages 831-842, 1983).
The present inventors, in view of this true state of affairs, have continued a diligent study in search of a material which is dispossessed of the drawbacks suffered by the conventional antithrombic macromolecular materials, possessed of outstanding antithrombic quality and biocompatibility, and excellent in physical strength. Specifically, they have prepared model animals having injured intima in their blood vessels and continued a deliberate observation on the model animals to find how the blood vessels recover from the injuries. They have consequently found the conditions which the artificial blood vessels ought to fulfill. This invention has been accomplished on the basis of this knowledge. This knowledge is that when the intima of a natural blood vessel sustains an injury, one layer of fibrin formed on the exposed internal elastic lamina inevitably undergoes thrombosis and, thereafter, the blood vessel is not clogged but is allowed to induce the covering of intima in a matter of only one week's time. On the basis of this knowledge, the inventors have noticed the fibrin temporarily formed on the internal elastic lamina after infliction of an injury on the intima as a material combining antithrombic quality with early healing. They have perfected this invention as the result.
An object of this invention, therefore, is to provide a novel antithrombic medical material, an artificial internal organ, and a method for the production of a material for promoting antithrombic quality.